Controlled release pharmaceutical formulations which provide for the uniform release of a medicament at a controlled rate over a desired extended period of time are of great benefit to both the patient and medical practitioner. Since the controlled release of many drugs is pH-dependent, certain dosage forms are not suitable for release in certain environments. For example, depending upon whether the controlled release is to be in the eyes, stomach, mouth, rumen, vagina, rectum, skin or gastrointestinal tract, the pH of the release environment can vary from neutral to acidic. For this reason, many controlled release systems that work in the human stomach do not work in the human intestinal tract and vice versa.
Numerous mechanisms have been employed for controlled release formulations. U.S. Pat. No. 3,458,622 to Hill discloses a controlled release tablet for the administration of medicinal agents over a prolonged period of up to about eight hours. This patent discloses a compressed tablet formed of a core containing a drug, a polymeric vinyl pyrrolidone, preferably polyvinyl pyrrolidone (PVP), and a carboxyvinyl hydrophilic polymer (hydrocolloid) such as those marketed under the trademark Carbopol, and a coating formed of the two polymeric substances on the core providing the controlled release effect by forming a complex under the action of water or gastric fluid. This complex is gel-like in consistency and retards the diffusion of the drug from the tablet.
U.S. Pat. No. 4,140,755 to Sheth et al. discloses a sustained release formulation in the form of sustained release tablets which are hydrodynamically balanced to have a bulk density (specific gravity) of less than one in contact with gastric fluid and which will therefore remain floating in gastric fluid which has a specific gravity of between 1.004 and 1.010. The Sheth et al. sustained release formulation contains a homogeneous mixture of one or more medicaments with one or more hydrophilic hydrocolloids, such as hydroxypropyl methyl cellulose having a viscosity of 4000 cps. The hydrocolloids when contracted with gastric fluid at body temperature form a sustained gelatinous mix on the surface of the tablet causing the tablet to enlarge and acquire a bulk density of less than one. The medicament is slowly released from the surface of the gelatinous mix which remains buoyant in the gastric fluid.
All of the medicament in the tablet disclosed in the Sheth et al. patent is released in the stomach.
Sawayanagi et al. (Chem. Pharm. Bull, 30(11):4213, 1982) have disclosed sustained release preparations for propanolol hydrochloride using poly[(1.fwdarw.4)-2-amino-2-deoxy-.beta.-D-glucose] (chitosan). The chitosan forms a gel matrix for the controlled release of the drug. However, these preparations are pH-dependent in that the gel is only formed in an acidic environment and the tablets completely disintegrated in ten minutes at pH 6.8.
Kawashima et al. (Chem. Pharm. Bull. 33(5):2107, 1985) and Miyazaki et al. (Chem. Pharm. Bull. 33(9):3986, 1985) disclose tablet preparations for aspirin and indomethacin, respectively, using acetic acid which is a necessary addition to form the chitosan-drug mixtures for use in sustained release formulations.
U.S. Pat. No. 4,221,778 to Raghunathan et al. discloses a substantially pH-independent controlled release mechanism known as the Pennkinetic.TM. system which employs ion exchange resins. In this system, the drug is adsorbed onto the ion exchange resin particles and thereafter the particles are coated with a diffusion barrier. Ions from the environment diffuse through the coating and displace the drug molecules which subsequently diffuse out. However, loading of the drug molecules onto the resin particles is often inefficient. Further, preparations with water soluble drugs are typically unstable because the drugs are easily washed off of the resin particles (known to be hydrophobic) during processing.
Angiotensin converting enzyme (ACE) inhibitors are known for their usefulness as antihypertensive agents. Typical ACE inhibitors include substituted proline derivatives disclosed in U.S. Pat. No. 4,105,776 to Ondetti et al.; azetidine-2-carboxylic acid derivatives disclosed in U.S. Pat. No. 4,046,889 to Ondetti et al.; phosphinylalkanoyl prolines disclosed in U.S. Pat. No. 4,168,267 to Petrillo; phosphinylalkanoyl substituted prolines disclosed in U.S. Pat. No. 4,337,201 to Petrillo; phosphonamidate substituted amino or imino acids disclosed in U.S. Pat. No.4,432,971 to Karanewsky et al.; carboxyalkyl dipeptide derivatives disclosed in U.S. Pat. No. 4,472,380 to Harris et al.; and the like. Formulation of these and other drugs into controlled release systems is very difficult.
Accordingly, a controlled release formulation and method suitable for the sustained release of a medicament, such as angiotensin converting enzyme inhibitors, in a wide range of pH environments for administration to mammalian species would be a welcome addition to the art.